PROJECT SUMMARY/ABSTRACT Progress in the early detection and treatment of cancer requires accurate model systems to further evaluate new, promising discoveries. Small animal, and in particular mouse, model systems are attractive to researchers for numerous reasons, including their ease of use and well-described platforms. Immunotherapy has revolutionized clinical oncology, but lacks pre-clinical models of the human immune system and human cancer to investigate new modalities and limitations/toxicities of treatment regimens. The ability to grow human tumors in immunodeficient mice (so-called patient-derived xenografts, or PDXs) allows researchers to work directly with human cancer tissue in a controlled setting. However, PDX models are limited by their lack of an intact immune system. The broad objective of this proposal is to validate an in vivo model to evaluate human tumors in the context of a complete and intact human immune system in a completely personalized and autologous fashion. Herein, we propose to: (1) validate the ability to establish humanized mice from patients with melanoma; (2) evaluate tumor growth and lymphocyte development in autologous human melanoma tumors established in humanized mice; and (3) validate the ability of this humanized system to serve as a model for cancer immunotherapy treatment response and toxicity. In each of these areas, we will leverage our multi- institutional team's individual expertise along with our institutional infrastructure to maximize the success of the experimental aims. Furthermore, we will participate in the Oncology Models Forum and utilize the NCIP Hub resources to ensure that the methodology, data, and biologic model systems that result from this project are made widely available to the general research community for future, hypothesis-driven research. Taken together, the studies described in this research proposal will meet multiple goals and address several unmet needs identified in this grant opportunity, thus significantly enhancing the applicability of a fully autologous and immunocompetent precision model system for use in translational oncology research.